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【结 构 式】 
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【分子编号】27942 【品名】3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride 【CA登记号】4568-71-2 |
【 分 子 式 】C13H16ClNOS 【 分 子 量 】269.79488 【元素组成】C 57.87% H 5.98% Cl 13.14% N 5.19% O 5.93% S 11.89% |
合成路线1
该中间体在本合成路线中的序号：(IV)Alkylation of 5-iodovanillin (I) with iodoethanol gave hydroxyethyl ether (II). This was condensed with vinyl ketone (III) in the presence of the thiazolium salt (IV) to produce the 1,4-diketone (V). Subsequent reduction of (V) with NaBH4 afforded 1,4-diol (VI), which was cyclized with trifluoroacetic acid in chloroform to furnish a mixture of cis and trans diaryltetrahydrofurans. The required trans isomer (VII) was isolated by column chromatography, and then treated with methanesulfonyl chloride and triethylamine to give mesylate (VIII). Further condensation of (VIII) with 4-chlorothiophenol (IX) provided sulfide (X). Finally, displacement of the iodine atom with CuCN in boiling DMF produced the title nitrile.
| 【1】 Cai, X.; et al.; (+-)-trans-2-[3-Methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N-hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (CMI-392), a potent dual 5-lipoxygenase inhibitor and platelet-activating factor receptor antagonist. J Med Chem 1998, 41, 11, 1970. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 38258 | 2-iodo-1-ethanol | 624-76-0 | C2H5IO | 详情 | 详情 | |
| (I) | 12758 | 4-Hydroxy-3-iodo-5-methoxybenzaldehyde; 5-Iodovanillin | 5438-36-8 | C8H7IO3 | 详情 | 详情 |
| (II) | 27940 | 4-(2-hydroxyethoxy)-3-iodo-5-methoxybenzaldehyde | C10H11IO4 | 详情 | 详情 | |
| (III) | 27941 | 1-(3,4,5-trimethoxyphenyl)-2-propen-1-one | C12H14O4 | 详情 | 详情 | |
| (IV) | 27942 | 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride | 4568-71-2 | C13H16ClNOS | 详情 | 详情 |
| (V) | 27943 | 1-[4-(2-hydroxyethoxy)-3-iodo-5-methoxyphenyl]-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione | C22H25IO8 | 详情 | 详情 | |
| (VI) | 27944 | 1-[4-(2-hydroxyethoxy)-3-iodo-5-methoxyphenyl]-4-(3,4,5-trimethoxyphenyl)-1,4-butanediol | C22H29IO8 | 详情 | 详情 | |
| (VII) | 27945 | 2-[2-iodo-6-methoxy-4-[(2S,5S)-5-(3,4,5-trimethoxyphenyl)tetrahydro-2-furanyl]phenoxy]-1-ethanol | C22H27IO7 | 详情 | 详情 | |
| (VIII) | 27946 | 2-[2-iodo-6-methoxy-4-[(2S,5S)-5-(3,4,5-trimethoxyphenyl)tetrahydro-2-furanyl]phenoxy]ethyl methanesulfonate | C23H29IO9S | 详情 | 详情 | |
| (IX) | 27947 | 4-chlorobenzenethiol | 106-54-7 | C6H5ClS | 详情 | 详情 |
| (X) | 27948 | (2S,5S)-2-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran | C28H30ClIO6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)In a related procedure, iodination of acetophenone (XI) gave (XII). Subsequent alkylation of (XII) with dibromoethane afforded bromoethyl ether (XIII), which was converted to sulfide (XIV) by condensation with 4-chlorothiophenol (IX). Mannich reaction of (XIV) with paraformaldehyde and dimethylamine hydrochloride produced tertiary amine (XV), which was quaternized to (XVI) with MeI. Elimination in the resulting ammonium salt (XVI) produced vinyl ketone (XVII). Diketone (XIX) was then obtained by condensation with trimethoxybenzaldehyde (XVIII) in the presence of thiazolium salt (IV). Reduction of both ketone groups of (XIX) using NaBH4 yielded diol (XX), which was further cyclized with orthophosphoric acid in refluxing benzene to furnish a diastereomeric mixture of cis and trans diaryltetrahydrofurans (XXI). Iodine displacement in (XXI) with CuCN produced the corresponding diastereomeric mixture of cyanides, from which the target trans isomer was isolated by column chromatography.
| 【1】 Ram, B.; et al.; (±)-Trans-2-[3-methoxy-4-(4-chlorophenyl thioethoxy)-5-cyanophenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran, a potent PAF-receptor antagonist. Tetrahedron 1999, 55, 33, 10163. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 | |
| (IV) | 27942 | 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride | 4568-71-2 | C13H16ClNOS | 详情 | 详情 |
| (IX) | 27947 | 4-chlorobenzenethiol | 106-54-7 | C6H5ClS | 详情 | 详情 |
| (XI) | 22604 | 1-(4-hydroxy-3-methoxyphenyl)-1-ethanone；Acetovanillone;4’-hydroxy-3’-methoxyacetophenone;1-(4-hydroxy-3-methoxyphenyl)ethanone | 498-02-2 | C9H10O3 | 详情 | 详情 |
| (XII) | 27949 | 1-(4-hydroxy-3-iodo-5-methoxyphenyl)-1-ethanone | C9H9IO3 | 详情 | 详情 | |
| (XIII) | 27950 | 1-[4-(2-bromoethoxy)-3-iodo-5-methoxyphenyl]-1-ethanone | C11H12BrIO3 | 详情 | 详情 | |
| (XIV) | 27951 | 1-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-1-ethanone | C17H16ClIO3S | 详情 | 详情 | |
| (XV) | 27952 | 1-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-3-(dimethylamino)-1-propanone | C20H23ClINO3S | 详情 | 详情 | |
| (XVI) | 27953 | 3-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-N,N,N-trimethyl-3-oxo-1-propanaminium iodide | C21H26ClI2NO3S | 详情 | 详情 | |
| (XVII) | 27954 | 1-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-2-propen-1-one | C18H16ClIO3S | 详情 | 详情 | |
| (XVIII) | 11136 | 3,4,5-Trimethoxybenzaldehyde | 86-81-7 | C10H12O4 | 详情 | 详情 |
| (XIX) | 27955 | 1-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione | C28H28ClIO7S | 详情 | 详情 | |
| (XX) | 27956 | 1-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanediol | C28H32ClIO7S | 详情 | 详情 | |
| (XXI) | 27957 | 2-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran | C28H30ClIO6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(B)From the starting carbaldehyde (I) two different pathways can be followed: 1) A solution of carbaldehyde (I) in ether is treated with the vinyl Grignard reagent (A) in THF and oxidized with activated manganese dioxide to afford enone derivative (II). The derivative is then coupled with methyl 4-formylbenzoate (III) in refluxing ethanol in presence of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (B) to yield diketone (IV). 2) Methyl 4-formylbenzoate (III) is treated with vinylmagnesium bromide (A) in THF, and oxidized with pyridinium dichromate to give methyl 4-acryloylbenzoate (V), which is coupled with carbaldehyde (I) by means of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (B) and triethylamine in DMF to yield directly diketone (IV). The final step is the cyclization of diketone (IV) to afford the pyrrole-benzoic acid derivative by treatment of the diketone with ammonium acetate in refluxing methanol and hydrolysis with NaOH in refluxing ethanol followed by neutralization with dilute HCl.
| 【1】 Tagami, K.; Nagai, M.; Tokuhara, N.; Hida, T.; Yoshimura, H.; Hibi, S.; Yamauchi, T.; Kikuchi, K.; Tai, K.; Syntheses and evaluation of naphthalenyl- and chromenyl-pyrrolyl-benzoic acids as potent and selective retinoic acid receptor alpha agonists. Bioorg Med Chem Lett 2000, 10, 7, 623. |
| 【2】 Tagami, K.; Yoshimura, H.; Nagai, M.; Hibi, S.; Kikuchi, K.; Sato, T.; Okita, M.; Okamoto, Y.; Nagasaka, Y.; Kobayashi, N.; Hida, T.; Tai, K.; Tokuhara, N.; Kobayashi, S. (Eisai Co., Ltd.); Fused-ring carboxylic acid derivs.. EP 0889032; US 6110959; US 6121309; WO 9734869 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (B) | 27942 | 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride | 4568-71-2 | C13H16ClNOS | 详情 | 详情 |
| (I) | 40989 | 5,8-dimethyl-2H-chromene-3-carbaldehyde | C12H12O2 | 详情 | 详情 | |
| (II) | 40990 | 1-(5,8-dimethyl-2H-chromen-3-yl)-2-propen-1-one | C14H14O2 | 详情 | 详情 | |
| (III) | 10170 | methyl 4-formylbenzoate | 1571-08-0 | C9H8O3 | 详情 | 详情 |
| (IV) | 40991 | 4-[4-(5,8-dimethyl-2H-chromen-3-yl)-4-oxobutanoyl]benzoic acid | C22H20O5 | 详情 | 详情 | |
| (V) | 35857 | methyl 4-acryloylbenzoate | C11H10O3 | 详情 | 详情 |